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The drug discovery process is currently undergoing a fundamental revolution as it embraces “functional genomics,” that is, high throughput genome- or gene-based biology. This approach provides improved means to identify genes and gene products which are associated with or causative of a disease/disorder. The identification of a disease-linked target (e.g., a gene variant) provides a tool with which to diagnose subjects who have the disease or are genetically predisposed to develop the disease. The identification of such disease-linked targets also facilitates the development of therapeutic agents which modulate the activity of these targets and thus provide means to ameliorate and/or treat the disease. Such therapeutic agents may also be used as prophylactic agents to delay and/or prevent the onset of disease in a subject.
Functional genomics relies heavily on high-throughput DNA sequencing technology and bioinformatics to identify gene sequences of potential interest from the numerous molecular biology databases available. There is, however, a continuing need to identify and characterize additional genes/gene variants and their encoded polypeptides/proteins, as targets for drug discovery.
Ferritin has two major functions: iron detoxification and sequestration and storage of intracellular iron (reviewed in Theil, 1987, Annu Rev Biochem. 56:289-315). The mammalian form of this molecule, a protein of ˜450 kDa, contains two smaller subunits, designated ferritin heavy polypeptide (FTH1) and ferritin light polypeptide (FTL). The genes encoding FTH1 and FTL have been mapped to human chromosomes 11q12q13 and 19q13.3-13.4, respectively. A functional ferritin molecule is comprised of twenty-four FTH1 and FTL subunits which form a soluble, hollow sphere. The mineral ferrihydite core of the sphere is able to store up to 4,500 atoms of iron. The FTH1 and FTL subunits are thought to have complementary functions with regard to iron storage. The FTH1 subunit possesses a specific ferroxidase activity following rapid uptake of iron and the FTL subunit is considered important for the initiation and stabilization of the ferritin-iron core (Harrison and Arosio, 1996, Biochim Biophys Acta. 1275:161-203).
Proteins which function in iron metabolism underlie several genetic disorders (reviewed in Sheth and Brittenham, 2000, Annu Rev Med. 51:443-64), including some neurodegenerative syndromes. Many of the neurodegenerative syndromes are characterized by extensive intracellular iron accumulation which leads to neuronal dysfunction and toxicity.